Gestational diabetes occurs in about 4% of pregnancies in the U.S. (Getahun, 2008), increasing with maternal age and body mass index (Engelgau et al., 1995). GDM is associated with increased risks of perinatal mortality and congenital malformations (Sepe et al., 1985), pregnancy-induced hypertension and FGR, but the causes are not well understood (American Pregnancy Association, 2004). Children of women with GDM are also at increased risk for obesity and abnormal glucose tolerance by the time of puberty (Schneider and Rayfield, 2002). Preeclampsia, the most common hypertensive disorder of pregnancy, defined by the triad of hypertension, proteinuria and edema, occurs in 6-10% of pregnancies and is the leading cause of maternal mortality in Western countries (Great Britain Department of Health, Why Mothers Die: Report on Confidential Enquiries into maternal Deaths in the United Kingdom 1994-1996. London, TSO, 1998). A characteristic feature of the disorder is that it usually resolves after delivery of the fetus and placenta. Progressive fetal growth restriction associated with preeclampisa is a leading cause of perinatal morbidity and mortality (National High Blood Pressure Education Program Working Group Report on High Blood Pressure in Pregnancy. Am J Obstet Gynecol 1990; 163:1691-1712). Current treatment options are limited and include bed rest, magnesium sulfate administration to prevent convulsions, and early delivery. The cause of preeclampsia remains uncertain but a primary role is attributed to the placenta and to poor placental perfusion resulting in hypoxia and increased oxidative stress.
Preeclampsia is commonly associated with fetal growth restriction (FGR), small-for-gestational-age (SGA) birth, and preterm delivery (Sibai et al., 2005) as well as gestational diabetes (Carpenter, 2007). The maternal syndrome of preeclampsia and its fetal counterpart, fetal growth restriction (FGR), present a continuing conundrum: while these conditions are associated with each other and with other de novo or preexisting metabolic abnormalities, the precise sequence of events and the causal mechanisms underlying these conditions and their long-term sequelae are uncertain. A predominant view is that preeclampsia is initiated by inadequate trophoblast invasion of the arterioles by the cytotrophoblast, which leads to incomplete remodeling of the uterine spiral arteries and to a state of placental hypoxia (Roberts et al., 1989; Conrad and Benyo, 1997; Gilbert et al., 2008). The poorly perfused placenta in turn synthesizes and releases vasoactive factors, including soluble VEGF receptor 1 (sVEGFR1, also known as soluble fms-like tyrosine kinase-1 or sFlt-1), soluble endoglin (sEng), angiotensin II type-1 receptor autoantibodies, and cytokines such as tumor necrosis factor-alpha, which generate widespread dysfunction of the maternal vascular endothelium, resulting in hypertension and other features of preeclampsia. Endothelium-derived relaxing and contracting factors maintain vascular homeostasis, and the ischemic placenta is believed to induce endothelial dysfunction in the maternal vasculature by altering the balance between angiogenic and antiangiogenic factors, in particular sFlt-1, in favor of the latter (Maynard et al., 2003, Karumanchi et al., 2005). Angiogenic factors include vascular endothelial growth factor (VEGF) and placental growth factor (PIGF). sFlt-1 appears early in the circulation, before the clinical onset of preeclampsia (Levine et al., 2006). Although the precise sequence of events in the placental release of sFlt-1 is uncertain (Karumanchi et al., 2004), the initiating event in preeclampsia is assumed to be reduced uteroplacental perfusion as a result of abnormal cytotrophoblast invasion of the spiral arterioles. The fact that preeclamptic symptoms develop during pregnancy and generally cease after delivery is taken as evidence that the placenta is the primary cause of the condition.
A well-characterized experimental model of preeclampsia involves clamping the uterine artery to produce a hypoxic condition in the placenta (the Reduced Uterine Perfusion Pressure, or RUPP model). RUPP-induced hypertension in the rat is associated with marked cardiovascular dysfunction similar to that seen in women with preeclampsia (Schlook et al., 2007) as well as an imbalance of angiogenic factors, including increased sFlt-1 and decreased VEGF and PIGF (Gilbert et al., 2007). Clinical evidence also indicates an imbalance between proangiogenic VEGF and PIGF, and antiangiogenic sFlt-1 in preeclampsia (Lam et al., 2005). Thus a working hypothesis is that the maladaptive overexpression of soluble VEGF receptor 1 (sVEGFR1) and its antagonism of VEGF bioactivity contribute to the deficient angiogenic response that results in PREEC-FGR. Plasma and amniotic fluid concentrations of sFlt-1 are increased in patients with preeclampsia and in placental sFlt-1 mRNA (Maynard et al., 2003). Increases in sFlt-1 and sEng predict preeclampsia, since concentrations rise before manifestations of overt symptoms of hypertension and proteinuria (Lam et al., 2005; Levine et al., 2006). Conversely, VEGF infusion attenuates the increased blood pressure and renal damage seen in pregnant rats overexpressing sFlt-1 (Li et al., 2007). In the pregnant rat, uteroplacental ischemia increases placental sFlt-1 and is associated with decreased VEGF and PIGF in late gestation; adenovirus-mediated combined increases in sFlt-1 and sEng also exacerbate the effects of either factor alone, resulting in fetal growth restriction as well as severe hypertension and proteinuria (Venkatesha et al., 2007). Markers of endothelial dysfunction, in particular nitric oxide (NO), are also associated with preeclampsia. Chronic NO synthase inhibition in pregnant rats leads to hypertension and associated peripheral and renal vasoconstriction, proteinuria, FGR, and increased fetal death (Gilbert et al., 2008).
In summary, considerable evidence supports the hypothesis of reduced placental perfusion as a cause of preeclampsia and FGR; similarly, the link between FGR, preeclampsia and later-onset vascular disease is thought to result from an initial state of reduced utero-placental perfusion (Granger et al., 2001). High rates of low birth weight (LBW) in the United States and other western countries are also attributed to defective uteroplacental perfusion rather than maternal malnutrition (Henriksen et al., 1997). In rats, placental insufficiency/ischemia induced by uterine artery ligation in mid- to late-gestation results in LBW offspring that are predisposed to develop hypertension (Alexander, 2003).
There are several limitations to this theory. First, the stimulus that initiates the failure of cytotrophoblasts to invade the spiral arterioles and the resulting reduction in placental perfusion is unknown. Second, maternal factors unrelated to the placenta also contribute to the risk of preeclampsia and SGA birth. For instance, preeclampsia is associated with the metabolic syndrome that includes chronic hypertension (Samadi et al., 2001), elevated serum triglycerides and free fatty acids, insulin resistance and glucose intolerance. Insulin resistance can also precede preeclampsia and is associated with the overall syndrome of preeclampsia. Triglyceride-rich lipoproteins associated with low-density lipoproteins are significantly increased in women who develop preeclampsia. Obesity is also strongly associated with preeclampsia and increased plasma triglyceride concentration, and can be associated with SGA, LGA, and preterm birth (Rajasingam et al., 2009). To determine whether metabolic derangements follow or precede placental ischemia, a study using the RUPP model found that metabolic syndrome-like derangements are not a direct consequence of RUPP but contribute to cardiovascular dysfunction in preeclampsia independently of poor placental perfusion. Third, other known correlates of preeclampsia are not satisfactorily explained on the hypothesis of poor placental perfusion including, e.g., the association of preeclampsia with neutrophils and neutrophilic activation (Cadden and Walsh, 2008; Tsukimori et al., 2008); low serum vitamin A (Ziari et al., 1996; Zhang et al., 2001; Wardle et al., 2001); hyperuricemia, which develops as early as 10 weeks of gestation in women who later develop preeclampsia (Koopmans et al., 2008; Bainbridge et al., 2009); headache (Contag et al., 2009; Facchinetti et al., 2009); and the long-term increased risk of cardiovascular disease (Craici et al., 2008). These observations call for new insights into the causes of preeclampsia, FGR/SGA birth and subsequent increased risks of vascular disease.